Our project is an epigenomic approach to understand the pathogenesis of Alzheimer's disease (AD), a degenerative disorder of neurons that is the most common cause of age-related dementia. Much prior emphasis in AD research has been on genetic studies, which have uncovered the fundamental involvement of the APP, APOE and PS1 genes. But with the exception of polymorphisms in APOE, known coding variants in these genes are quite rare, and the existing data do not fully account for the heritability of AD in the general population. Additional chromosomal loci that influence AD susceptibility have been uncovered by genome scanning, but while several of these loci have been confirmed in multiple studies, the causative or predisposing genetic variants have not been clearly pinpointed. New approaches are needed to get through this roadblock, and we believe that the novel combined epigenetic-genetic strategy that we propose here can be transformative in solving this problem. The equally important question of why AD is inexorably progressive, at least in our current ignorance of effective treatments, also has no clear answer. It is safe to say that progression to neuronal cell death occurs after a threshold of cellular damage, but what the crucial damage is and how it accumulates over time are largely unknown. A component of this damage may be epigenetic, including altered DNA methylation. In this collaborative and multi-disciplinary project we will bring genome-wide epigenomic profiling methods to bear on 2 working hypotheses. First, we postulate that epigenetic aberrations in the brain are involved in the progression of AD, and that genome-wide analysis of DNA methylation in cerebral cortex from early to mid-stage AD cases, compared to control brains, will pinpoint biologically relevant loci that are recurrently affected by gains or losses of net DNA methylation (affecting both alleles) in this disease. Second, our genome-wide epigenetic analysis will pay off, at no additional cost, in the identification of loci with sequence-dependent allele-specific DNA methylation (ASM) and allele- specific gene expression (ASE), thus pinpointing regulatory polymorphisms that act to establish inborn and stable inter-individual differences in gene expression in brain cells, in part through haplotype- dependent epigenetic modifications. We expect that among these sequence variants will be some that affect inter-individual differences in susceptibility to AD. The list of candidate loci from our epigenomic profiling will be brought forward for narrowly focused and thus cost efficient genetic fine mapping in the valuable well characterized cohorts of AD case and controls that are available through the long- standing collaborative relationship of the 2 PI's. Public Health Relevance: Our project is an epigenomic approach to understand the pathogenesis of Alzheimer's disease (AD), a degenerative disorder of neurons that is the most common cause of age-related dementia. By profiling DNA methylation in normal brains and in brains affected by AD we will determine whether recurrent changes in DNA methylation play a role in the inexorable progression of this disease. From the same epigenomic data we will identify a set of genes with genetically determined differences in DNA methylation, which we will directly test as candidates for causing inter-individual differences in susceptibility to AD, using large family-based and case-control cohorts of elders at risk for this disease.